The etiology of neuronal degeneration in Huntington's disease and other neurodegenerative diseases may involve a complex interplay between energy impairment and oxidative damage. There is substantial evidence for metabolic dysfunction in Huntington's disease. A major advance in studying Huntington's disease was the development of transgenic models. In the present proposal we will determine whether there are defects in oxidative phosphorylation in transgenic animal models of HD. We will make direct measurements of ATP, phosphocreatine and lactate. We will measure the electron transport enzymes as well as enzymes involved in the tricarboxylic acid (TCA) cycle. We will utilize both proton and 13C glucose NMR spectroscopic studies to help to localize a defect in vivo. We will also utilize these techniques ex vivo. We will determine whether there is evidence of oxidative damage by measuring 8-hydroxy-2- deoxyguanosine, protein carbonyls, 3-nitrotyrosine, malondialdehyde and the conversion of salicylate to dihydroxybenzoic acid in tissue. We will also carry out immunocytochemical studies for oxidative markers. We will utilize microdialysis to determine whether there is evidence of increased hydroxyl radical generation in vivo. We will examine animals at 4, 8, and 12 weeks of age which are time points corresponding to a presymptomatic phase, a symptomatic phase and advanced illness. We will determine whether therapeutic interventions which may improve energy metabolism can improve both functional outcome as well as survival in transgenic HD mice. We will evaluate the effects of coenzyme Q10, nicotinamide and creatine. Lastly we will utilize mice deficient in JNK-3 kinase and mice overexpressing bcl-2 to determine whether these mice are resistant to striatal lesions produced by the mitochondrial toxins malonate or 3-nitropropionic acid (3-NP), and whether protection is associated with reductions in biochemical markers of oxidative damage. These studies will provide direct evidence whether there is a metabolic defect and oxidative damage in a transgenic animal model of HD. They also have the potential of leading to new therapeutic interventions which might be useful in the treatment of HD.